Transcript Super Bug by Dr. Sarma

దాసస్తేహం దేహదృష్ట్
య ాస్మి శంభో
జాతస్తేశో జీవదృష్ట్
య ా త్రిదృష్ట్యా
సర్వస్యాతినాతి దృష్ట్
య ా
తవమేవ
త్వవవం మే ధీర్నిశ్చితా సర్వ శాస్త్రైః
||
daasasthae aham daehadrishtya asmi Sambho
jaathasthaeso jeeva drishtyaa thri drishtyae
sarvasya athman athma drishtyaa thwamaeva
thwaevam mae dheer nishchithaa sarva saasthraih ||
O! Lord, the three eyed one (who is the all knower of the
past, present and future)! In the form of this physical
equipment, the body, I am the servant of You and thus of
all. In the form of the life principle with in me, I am the
part and parcel of You and thus of all. In the form the
soul, You are within me and similarly in every other being
or animal or thing that I behold. I have arrived at this
conclusion after thorough reflection in my intellect illuminated by all the sacred texts.
“The greatest possibility of evil in selfmedication is the use of too small doses so
that instead of clearing up infection, the
microbes are educated to resist penicillin
and a host of penicillin-fast organisms is
bread out which can be passed to other
individuals and from them to others until
they reach someone who gets a septicemia
or a pneumonia which penicillin cannot
save.”
Sir Alexander Fleming … 1954
M.D., M.Sc.(Canada), FIMSA,
Senior Consultant Physician &
Cardio-Metabolic Specialist
Food
Venti
lators
Air,
Dust
Endo
scopes
Water
Patient
Cathe
ters
Disinfe
ctants
IV
Fluids
Wash
basins
Toilets
Cell Wall
 Lactams (Penicillins, Cephalosporins,
Carbapenems, Monobactams) Vancomycin, Bacitracin
Protein
Synthesis
Macrolides, Lincosamides, Chloramphenicol,
Tetracycline, Aminoglycosides, Mupirocin, Linezolid
Nucleic
Acid synth
Rifampin, Metronidazole
DNA
Synthesis
Quinolones, Novobiocin
Cell
Membrane
Polymyxin B, Gramicidin, Daptomycin
Inappropriate empiric antibiotic therapy can lead to
increases in:
– mortality
– morbidity
– length of hospital stay
– cost burden
– resistance selection
A number of studies have demonstrated the benefits
of early use of appropriate empiric antibiotic therapy
for patients with nosocomial infections
Inappropriate antibiotic therapy can be defined
as one or more of the following:
– ineffective empiric treatment of bacterial
infection at the time of its identification
– the wrong choice, dose or duration of Rx.
– use of an antibiotic to which the pathogen
is resistant
18
14
12
Resistance
Number of agents approved
16
10
8
6
4
2
0
0
1983-87
1988-92
1993-97
1998-02
2003-05
2008
Bars represent number of new antimicrobial agents approved by the FDA during that period
•Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286;
•New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912
• Uncontrolled, improper and indiscriminate use of
antibiotics for therapy and prophylaxis
• Inadequate lengths of therapy
• unnecessary use, lack of activity, insufficient doses
• low penetration to body sites
• Poor patient compliance
• Poor hand hygiene & failure of infection control measures
• Excessive use of cleaners, detergents & anti bacterials
• Antibiotics in livestock, animals, birds & agriculture
Antibiotics are the medical miracle of the last 50yrs
• Selection Pressure – “Survival of the fittest”
• Innate genetic mutation
• Destruction or Inactivation (-Lactamase)
• Efflux of the antibiotic that entered the bacteria
• Accepting resistance genes from other bacteria
• Genetic Transfer by Plasmids, Transposons
• Conjugation, Transformation and Transduction
Penicillinase
Plasmid
Gene for -Lactamase
This organism can freely grow
in the presence of Penicillin
–Lactam Ring
Active
–Lactamase
Inactive
Structurally modified antibiotic target site,
resulting in:
– Reduced antibiotic binding
– Formation of a new metabolic pathway
preventing metabolism of the antibiotic
Antibiotics normally bind to specific binding
proteins on the bacterial cell surface
Antibiotic
Binding
Target site
Cell wall
Interior of organism
Antibiotics are no longer able to bind to modified
binding proteins on the bacterial cell surface
Antibiotic
Modified target site
Cell wall
Changed site: blocked binding
Interior of organism
Altered uptake of antibiotics, resulting in:
• Decreased permeability
• Increased efflux
Antibiotics normally enter bacterial cells via porin
channels in the cell wall
Antibiotic
Porin channel
into organism
Cell wall
Interior of organism
New porin channels in the bacterial cell wall do not
allow antibiotics to enter the cells
Antibiotic
New porin channel
into organism
Cell wall
Interior of organism
Antibiotics enter bacterial cells via
porin channels in the cell wall
Porin channel
Antibiotic
through cell wall
Entering
Entering
Cell wall
Interior of organism
Once antibiotics enter bacterial cells, they are
immediately excluded from the cells
via active pumps
Antibiotic
Porin channel
through cell wall
Entering
Exiting
Cell wall
Interior of organism
Active pump
Antibiotic inactivation
• Bacteria acquire genes encoding enzymes
that inactivate antibiotics
Examples include:
• -Lactamases
• Aminoglycoside-modifying enzymes
• Chloramphenicol acetyl transferase
Inactivating enzymes target antibiotics
Antibiotic
Enzyme
Binding
Target site
Cell wall
Interior of organism
Enzymes bind to antibiotic molecules
Enzyme
binding
Antibiotic
Enzyme
Binding
Target site
Cell wall
Interior of organism
Enzymes destroy antibiotics or prevent binding to target sites
Antibiotic
destroyed
Antibiotic altered,
binding prevented
Antibiotic
Enzyme
Target site
Cell wall
Interior of organism
-lactam
Glycopeptide
Aminoglycoside
Tetracycline
Chloramphenicol
Macrolide
Sulphonamide
Trimethoprim
Quinolones
Modified target
Altered uptake
Drug inactivation
+
+
–
–
+
++
+
+
–
++
++
++
++
–
–
–
+
+
Three mechanisms of -lactam antibiotic
resistance are recognised:
• Reduced permeability
• Inactivation with -lactamase enzymes
• Altered penicillin-binding proteins (PBPs)
AmpC and Extended-Spectrum -lactamase
(ESBL) production are the most important
mechanisms of -lactam resistance in
nosocomial infections
The antimicrobial and clinical features of these
resistance mechanisms are highlighted in the
following slides
Worldwide problem:
• Incidence increased from 17% to 23% between 1991
and 2001 in UK
Very common in Gram-negative bacilli
AmpC gene is usually sited on chromosomes, but
can be present on plasmids
Enzyme production is either constitutive (occurring
all the time) or inducible (only occurring in the
presence of the antibiotic)
Pfaller et al. Int J Antimicrob Agents 2002;19:383–388;
Sader et al. Braz J Infect Dis 1999;3:97–110; Livermore et al. Int J Antimicrob Agents 2003;22:14−27
An increasing global problem
Found in a small, expanding group of
Gram-negative bacilli, most commonly
the Entero-bacteriaceae spp.
Usually associated with large plasmids
Enzymes are commonly mutants of TEM- and
SHV-type -lactamases
Jones et al. Int J Antimicrob Agents 2002;20:426–431; Sader et al. Diagn Microbiol Infect Dis 2002;44:273–280
Inhibited by -lactamase inhibitors
Usually confer resistance to:
• 1, 2 and 3rd generation Cephalosporins eg. Ceftazidime
• Monobactams eg. Aztreonam
• Carboxypenicillins eg. Carbenicillin
Varied susceptibility to Piperacillin / Tazobactam
Typically susceptible to Carbapenems and Cephamycins
Often non-susceptible to fourth generation Cephalosporins
Genomic Islands
e.g. Escherichia Coli
Prophages
Common: 4.1 Mb
K12 Islands: 0.53 Mb
0157:H7 Islands: 1.34 Mb
Conjugative
Transposons (gram +ve)
Minimal species
Genomic backbone
Insertion Sequences
Transposons
Super Integrons
(Mainly  Protobacteria)
Integrons
Infectious Disease
Society of America
Superbugs – Resistant to two or
more wide spectrum antibiotics
– Acintobactor baumannii
– Pseudomonas aeruginosa
– ESBL-producing
Enterobacteriaceae
– Klebsiella pneumoniae
(carbapenemase producing)
– Methicillin Resistant
Staphylococcus aureus (MRSA)
– Vancomycin Resistant
Enterococcus (VRE), VRSA
– NDM1 – Escherichia coli
•1. Infectious Diseases Society of America. Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews.
http://www.idsociety.org/pa/IDSA_Paper4_final_web.pdf. July, 2004. Accessed March 17, 2007. 2. Talbot GH, et al. Clin Infect Dis. 2006;42:657-68.
MRSA (Staph. aureus)
Streptococcus pneumoniae
ESBL Escherichia coli
MRSA
NDM1 – Esch. coli
Grundmann H et al. Lancet 2006;368:874.
Published Online - August 11, 2010
• Gram-negative Enterobacteriaceae
• Resistance to Carbapenem & other antibiotics
• Conferred by New Delhi Metallo β Lactamase-1
• Called as NDM-1
• Potentially a major global health problem
• The prevalence of NDM-1 was investigated
• Multidrug resistant E. coli in India, Pakistan, & UK
• In India - Chennai, Haryana
• Carbapenems resistance gene blaNDM-1 by PCR
• 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the
UK, and 73 in other sites in India and Pakistan. NDM-1 was
mostly found among Escherichia coli (36) and Klebsiella
pneumoniae (111), which were highly resistant to all antibiotics
except to Tigecycline and Colistin.
• Most isolates carried the NDM-1 gene on plasmids
• Those from UK and Chennai were readily transferable whereas
those from Haryana were not conjugative.
• Many of the UK NDM-1 positive patients had travelled to India
or Pakistan within the past year.
• The potential of NDM-1 to be a worldwide public health
problem is great. Co-ordinated international effort is needed.
Lancet Infect Dis 2010; 10: 597–602
Lancet Infect Dis 2010; 10: 597–602
Lancet Infect Dis 2010; 10: 597–602
Lancet Infect Dis 2010; 10: 597–602
Antibiotic resistance in the hospital or community setting
is increasing at an alarming rate and the following steps
are essential to counter this menace
• Selecting the most appropriate antibiotic based on the
patient, risk factors, suspected infection and resistance
• Administering antibiotics at the right dose and duration
• Changing antibiotic dosage or therapy based on resistance
• Recognising that prior antimicrobial administration is a risk
factor for the presence of resistant pathogens
• Knowing ones area’s antimicrobial resistance profile and
choosing antibiotics accordingly
Cosgrove et al. Arch Intern Med 2002;162:185–190
Hand washing plays an important role in
nosocomial pneumonias
Wash hands before and after suctioning,
touching ventilator equipment, and/or coming
into contact with respiratory secretions.
Use a continuous subglottic suction ET tube
for intubations expected to be > 24 hours
Keep the HOB elevated to at least 30o
unless medically contraindicated
• Dalbavancin
• Oritavancin
• Telavancin
• Garenoxacin (FQ)
• Ceftobiprole (Zeftera®)
• Daptomycin (Cubicin®)
• Ceftaroline, Faropenem
Malabarba A et al. J Antimicrob Chemother. 2009